John Silke-Projects

John Silke-Projects

Projects

John Silke-Projects

We are taking several approaches to explore the best way that IAP antagonists can be used in the clinic to treat cancer. This is an area of intense research world-wide but we have unique advantages including:

Access to amazing patient-derived xenograft resources.

A longstanding collaboration with TetraLogic Pharamceuticals Corporation which is developing birinapant, an IAP-antagonist, in clinical trials.

The institute’s high throughput screening facility.

Using these reagents we are looking for the cancer types most responsive to birinapant killing and novel drug combinations that can overcome the resistance of other cancer types.

What role do IAPs and RIPK kinases play in generating an inflammatory response?

We have shown that IAPs and RIPK2 play an important role in regulating signalling from NOD receptors, essential intracellular receptors that detect and respond to bacterial products. We are exploring a small molecule approach to explore this pathway and with collaborators at the institute we have developed and characterised a new RIPK2 inhibitor.

This has a fascinating mode of action: it delays signalling events such as NF-κB activation by only an hour or less, but completely inhibits the production of inflammatory cytokines by this pathway. We are exploring this further with mass spectrometry approaches.

cIAPs and RIPK1 play important roles in regulating the signalling outcome downstream of TNF/TNFR1 activation. We have a long-standing interest in understanding how they function in this role, using a combination of genetics, small molecule inhibitor and mass spectrometry approaches.

More recently we have expanded our purview of this fascinating signalling paradigm by exploring the role of other regulators of this pathway including the linear ubiquitin assembly complex comprising the proteins SHARPIN, HOIL-1 and HOIP.